tbuckley/cabot-search huggingface dataset:
Abstract 1125: Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab
Authors: Tyler Joseph Alban, Nadeem Riaz, Prerana Parthasarathy, Vlad Makarov, Slav Kendall, Seong-Keun Yoo, Rachna Shah, Nils Weinhold, Raghvendra Srivastava, Xiaoxiao Ma, Chirag Krishna, Edward Garon, Wallace Akerley, Ben Creelan, Nivedita Aanuren, Diego Chowell, William Geese, Naiyer Rizvi, Timothy Chan
Journal: Cancer Research (2023)

Abstract Immune checkpoint blockade (ICB) therapy is a cornerstone of oncologic treatment for patients with advanced stage non-small cell lung cancer (NSCLC) and other malignancies. Neoantigen immunoediting drives ICB efficacy, yet how tumor evolution and neoantigen immunogenicity shape treatment response remains poorly understood. To address these questions, we conducted a prospective clinical trial of NSCLC patients treated with nivolumab. We assessed genomic alterations in tumors from 58 patients and performed large-scale immune epitope analyses, before and during treatment (CheckMate153, CA209-153). Tumors were analyzed by whole-exome and transcriptome sequencing. In responding patients, loss of mutation and neoantigen burden early during therapy was associated with clinical benefit. We evaluated the immunogenicity of 1,453 candidate neoantigens and identified 502 neopeptides that bound to MHC I and 196 neopeptides that were immunogenic and recognized by T cells in the setting of nivolumab treatment. These T cell reactive neoantigens were differentially present in clonal populations that underwent distinctive evolutionary trajectories across responders and nonresponders. Mapping these neoantigens to tumor clonal dynamics and clinical response revealed strong selection against immunogenic mutations compared to non-immunogenic mutations. We used this large collection of neoantigens to build ImmunoSEEK, a machine learning-based neoantigen prediction model and validated it using an orthogonal set of neoantigens. Changes in the genomic and neoantigen immunogenicity landscapes were accompanied by temporal changes in the tumor microenvironment. Nivolumab-induced microenvironmental evolution in NSCLC shared some similarities with that in melanoma, yet critical differences in immunologic programs were apparent from comparative network analysis between tumor types. This study provides unprecedented molecular portraits of the genomic and neoantigen landscapes underlying nivolumab’s mechanism of action. Citation Format: Tyler Joseph Alban, Nadeem Riaz, Prerana Parthasarathy, Vlad Makarov, Slav Kendall, Seong-Keun Yoo, Rachna Shah, Nils Weinhold, Raghvendra Srivastava, Xiaoxiao Ma, Chirag Krishna, Edward Garon, Wallace Akerley, Ben Creelan, Nivedita Aanuren, Diego Chowell, William Geese, Naiyer Rizvi, Timothy Chan. Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1125.
Abstract 1586: The potential therapeutic effect of the Rac/Cdc42 inhibitor MBQ-167 in glioblastoma<i>in vitro</i>
Authors: Derealise Garcia Almedina, Nilmary Grafals-Ruiz, Suranganie Dharmawardhane, Anamaris Torres-Sanchez
Journal: Cancer Research (2023)

Abstract Glioblastoma is a highly aggressive astrocytoma known to form the most lethal type of primary brain tumor. Therapeutic options are limited because 94% of diagnosed patients survive less than five years. Glioblastoma malignancy is attributed to uncontrolled cellular proliferation, increased angiogenesis, apoptosis resistance, and local invasion. The Homologous small GTPases of the Rho family, Rac1 and Cdc42, are critical regulators of the invasion and migration of glioblastoma cells. Previous studies have found a correlation between the high expression of Rac and CDC42 and the highly invasive characteristics of GBM in vivo. Our group characterized the small molecule compound MBQ-167 as a potent dual inhibitor of Rac and Cdc42 in breast and pancreatic cancer and have shown its utility in cell and mouse models of metastasis. In this project, we tested the hypothesis MBQ-167 is also a valid therapy option for glioblastoma. The T98G glioblastoma cell line was treated with varying concentrations (62 nM to 1000 nM) of MBQ-167 for 24 hrs, and effects on Rac/PAK activation (at 24 hours) was determined through active GTP bound Rac pulldowns, cell viability (at 48 and 96 hours) through MTT assays, and cellular migration (at 12, 24, and 48 hours) through wound healing assays. Results show that 250 nM of MBQ-167 inhibits Rac and PAK activation by 50% as well as cell viability at both time points (48 and 96 hours). MBQ-167 (150 nM-500 nM) also blocked glioblastoma cell migration at 12, 24, and 48 hours. Taken together, these results confirm that MBQ-167 is a viable inhibitor in glioblastoma. Citation Format: Derealise Garcia Almedina, Nilmary Grafals-Ruiz, Suranganie Dharmawardhane, Anamaris Torres-Sanchez. The potential therapeutic effect of the Rac/Cdc42 inhibitor MBQ-167 in glioblastomain vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1586.
Abstract 3656: A multi-scale approach to quantitatively evaluate the SMAD signaling pathway
Authors: Ernest Heimsath, Lisa Arvidson, Reginaldo Prioli, Antony Wood
Journal: Cancer Research (2023)

Abstract Angiogenesis and cell proliferation are fundamental biological processes whose pathologic states represent two hallmarks of cancer. Central to controlling both processes is the TGF-β/BMP signaling pathway, for which the SMAD proteins serve as major downstream effector molecules. Upon ligand-binding, TGF-β or BMP type I/II receptor heterotetramers phosphorylate receptor-regulated SMADs (R-SMADs). TGF-β-receptor binding leads to SMAD2/3 phosphorylation, whereas BMP-receptor binding induces phosphorylation of SMADs 1/5/8. Phosphorylated SMADs (pSMADs) then form a complex with the co-SMAD SMAD4 at which point they undergo nuclear translocation, where they function as transcriptional modulators of target genes. The magnitude of SMAD phosphorylation and functional output (e.g., stimulated angiogenesis or attenuated cell proliferation) depends on both the ligand concentration, as well as the duration of exposure. In this study, we quantitatively evaluate the phosphorylation states of R-SMADs, as well as their downstream biological effects at three different biological scales: 1) biochemical, 2) cellular, and 3) tissue/3D models. At the biochemical level, the temporal and dose-dependent phosphorylation of R-SMADs in response to growth factor stimulation can be quantified using a quantitative ELISA approach. Growth factor stimulation can be quantified at the cellular level by high content imaging of SMAD phosphorylation and nuclear translocation, while simultaneously monitoring cell proliferation rates. Lastly, high-resolution confocal imaging can be employed to observe developmental consequences of phospho-SMAD signaling using a HUVEC-based 3D angiogenesis model system. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Ernest Heimsath, Lisa Arvidson, Reginaldo Prioli, Antony Wood. A multi-scale approach to quantitatively evaluate the SMAD signaling pathway. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3656.
Abstract 5832: Integrinα5 mediates the direct heterocellular interaction between cancer cells and cancer-associated fibroblasts and promotes peritoneal metastasis of diffuse-type gastric carcinoma
Authors: Hideki Yamaguchi, Shingo Miyamoto, Yoshiko Nagano, Makoto Miyazaki, Yuko Nagamura
Journal: Cancer Research (2023)

Abstract Diffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric cancer characterized by rapid infiltrative growth and frequent peritoneal metastasis. Peritoneal metastasis is the main cause of poor prognosis and decreased quality of life for patients with DGC. Histologically, DGC tumor lesions are associated with massive fibrotic stroma caused by the extensive proliferation of cancer-associated fibroblasts (CAFs). Peritoneally metastasized tumors of DGC are also accompanied by abundant fibrotic stroma and CAFs. CAFs are known to promote the progression of DGC by enhancing the growth, invasion, and dissemination of tumor cells. Previously, we reported that the direct heterocellular interaction between cancer cells and CAFs is necessary for the invasion and peritoneal metastasis of DGC. In this study, we aimed to identify and target the molecules that mediate such direct heterocellular interaction. Monoclonal antibodies (mAbs) against intact DGC cells were generated and subjected to high-throughput screening to obtain mAbs that block the adhesion of DGC cells to CAFs. As a result, several such inhibitory mAbs were obtained. Immunoprecipitation and mass spectrometry revealed that all mAbs recognized integrin α5 complexed with integrin β1. Blocking integrin α5 in DGC cells abrogated the adhesion of DGC cells to CAFs. Similarly, blocking fibronectin, a ligand of integrin α5β1, deposited on CAFs blocked the heterocellular adhesion. Furthermore, administration of mAbs or knockout of integrin α5 in DGC cells suppressed their invasion led by CAFs in vitro and peritoneal metastasis in a mouse xenograft model. Analysis of the public database revealed that integrin α5 and fibronectin were highly expressed in DGC. In addition, integrin α5 and fibronectin expression levels were correlated with worse overall survival in DGC patients. Taken together, these results show that integrin α5 mediates the heterotypic cancer cell-CAF interaction during peritoneal metastasis of DGC and may thus be a promising therapeutic target. Citation Format: Hideki Yamaguchi, Shingo Miyamoto, Yoshiko Nagano, Makoto Miyazaki, Yuko Nagamura. Integrinα5 mediates the direct heterocellular interaction between cancer cells and cancer-associated fibroblasts and promotes peritoneal metastasis of diffuse-type gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5832.
Abstract 5254: Topical inhibition of UV-induced PD-L1 expression and inflammatory signaling by the small molecule inhibitor BMS-202
Authors: Prajakta Vaishampayan, Jana Jandova, Yuchen (Ella) Ai, Viktoria Kirschnerova, Clara Curiel-Lewandrowski, Georg T. Wondrak, Sally E. Dickinson
Journal: Cancer Research (2023)

Abstract Immune evasion is a molecular hallmark of cancer, and overexpression of the immune checkpoint protein PD-L1 (CD274) has been documented in several tumors including cutaneous squamous cell carcinoma (cSCC). Notably, while baseline levels of PD-L1 in normal human epidermis are low, acute solar-simulated light (SSL) exposure increases the expression of this protein in epidermal keratinocytes, an effect which can be replicated in cultured keratinocytes and in mouse models. While current immunotherapies targeting the PD-1/PD-L1 axis using monoclonal antibodies are providing therapeutic benefits in many cancers including cSCC, small molecule inhibitors are also being developed to target PD-L1 which may be amenable for topical formulation and therefore early intervention with reduced systemic exposure. We have recently tested one such molecule, BMS-202, in vitro and in vivo. BMS-202 application to keratinocytes in culture inhibits UV-induced PD-L1 RNA and protein expression. Notably, exposure to this inhibitor also reduced UV-induced stress signaling as measured by AP-1 luciferase assay in cultured keratinocytes. Topical application of BMS-202 to immunocompetent SKH-1 mouse skin resulted in significant inhibition of SSL-induced epidermal PD-L1 as determined by immunoblot analysis. NanoString nCounter Pathway™ transcriptomic analysis of full-thickness SKH-1 mouse skin shows strong inhibition of SSL-induced inflammatory responses, chemokine activity, innate immune response and NF-κB activation in BMS-202 treated samples compared to SSL-only controls. Our results indicate that early intervention against PD-L1 expression/activity could be a viable target for skin cancer photochemoprevention. Topical application of small molecule PD-L1 inhibitors such as BMS-202 may provide novel treatment options for populations at high risk for cSCC. Citation Format: Prajakta Vaishampayan, Jana Jandova, Yuchen (Ella) Ai, Viktoria Kirschnerova, Clara Curiel-Lewandrowski, Georg T. Wondrak, Sally E. Dickinson. Topical inhibition of UV-induced PD-L1 expression and inflammatory signaling by the small molecule inhibitor BMS-202. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5254.
Abstract 124: Autocrine signaling extends PD-L1 expression in NSCLC following an active immune response
Authors: Taylor M. Bursell, Sandhya Prabhakaran, Kimberly Luddy, Julian Pineriro, Rafael Bravo, Jeffrey West, Mark Robertson-Tessi, Aner Beg, Jhanelle Gray, Scott Antonia, Robert Gatenby, Alexander Anderson
Journal: Cancer Research (2023)

Abstract Checkpoint inhibitors disrupting the PD-1/PD-L1 axis are used in multiple cancer subtypes. However, not all patients respond, and predictive biomarkers are needed to better stratify patients. PD-L1, the most studied biomarker, has given mixed results. The complexity of the immune response and plastic nature of PD-L1 expression on tumor and immune cells contributes to the heterogeneity of success. Not all malignant epithelial cells express PD-L1: some express it only when the correct signal is present, while others have constitutive expression. Additionally, the PD-L1 protein has multiple functions outside immune regulation, making its dynamics difficult to predict. In this study, we investigate these complex PD-L1 dynamics through a unique combination of in vitro studies and mathematical modeling simulations. IFN-γ, a pleotropic cytokine released by activated immune cells, induces PD-L1 expression in some tumor cells. Chronic IFN-γ results in long-term PD-L1 expression. However, relaxation dynamics following removal of IFN-γ remains unexplored. We show that PD-L1 relaxation depends on autocrine signaling, demonstrated by multiple in vitro assays seeded with varying population densities. Following 48h IFN-γ treatment, sub-confluent tumor cell populations demonstrated increased duration of PD-L1 expression, linking cell density to PD-L1 expression. Conditioned-media from A549 cells previously treated with IFN-γ induced PD-L1 on IFN-γ naïve tumor cell populations, indicative of autocrine signaling not previously identified. To reinforce our in vitro findings, we develop a hybrid agent-based model (ABM) to study PD-L1 dynamics. Tumor cells have variable PD-L1 expression and IFN-γ is modeled via reaction-diffusion. IFN-γ triggers tumor cells to secrete a diffusible factor that promotes PD-L1 expression. Initial fits of the ABM capture in vitro data dynamics for different conditions. In this ongoing project, we plan to identify the underlying mechanism responsible for extended PD-L1 expression in NSCLC cells, including investigation into specific molecular pathways. Identifying the cause for this phenomenon could help clinicians improve targeted therapy and introduce a potential avenue to enhance treatment in patients responsive to checkpoint inhibitors. Citation Format: Taylor M. Bursell, Sandhya Prabhakaran, Kimberly Luddy, Julian Pineriro, Rafael Bravo, Jeffrey West, Mark Robertson-Tessi, Aner Beg, Jhanelle Gray, Scott Antonia, Robert Gatenby, Alexander Anderson. Autocrine signaling extends PD-L1 expression in NSCLC following an active immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 124.
Abstract 1589: Characterization of polyaminohydroxamic acids and polyaminobenzamides as inhibitors of HDAC10
Authors: Tracy Murray Stewart, Jackson R. Foley, Patrick M. Woster, Robert A. Casero
Journal: Cancer Research (2023)

Abstract Elevated polyamine levels are essential for continual proliferation of cancer cells. Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd), of which extracellular sources can be abundant, particularly in the colonic lumen. We previously demonstrated that exogenously supplied N8-AcSpd can support tumor cell growth through HDAC10-mediated deacetylation into spermidine, which is then redistributed within the polyamine interconversion pathway to maintain homeostasis.In the current study, we investigate the utility of polyamine-based hydroxamic acids (PAHAs) and benzamides (PABAs) as pharmacological inhibitors of HDAC10-mediated polyamine deacetylation. Incorporation of the polyamine moiety enables these compounds to enter the cell selectively through the polyamine transport system, which is upregulated in cancer cells. A total of 42 compounds, including 21 PAHAs and 21 PABAs, were screened for HDAC10 inhibition using a cell-based growth assay in which polyamine-depleted, growth-arrested cells are exposed to N8-AcSpd: in the presence of HDAC10 activity, this polyamine is deacetylated and proliferation is restored. Several compounds in our screen inhibited HDAC10 activity in this assay, as indicated by a lack of growth rescue, and were selected for further analysis in which treatment was expanded over a range of doses, thereby allowing a dose-dependent evaluation and comparison of sensitivity. HPLC-based analysis of cell lysates functionally confirmed that deacetylation of N8-AcSpd into spermidine was inhibited by the test compounds. Finally, specificity of the selected PAHAs and PABAs for HDAC10 was evaluated by immunoblotting for increased acetylation of the substrates of related HDACs, including histones H3 and H4, and alpha-tubulin. These studies provide a basis for future drug design strategies targeting the polyamine deacetylase activity of HDAC10 as an antitumor strategy, which may be particularly important in the context of polyamine-blocking therapies. Citation Format: Tracy Murray Stewart, Jackson R. Foley, Patrick M. Woster, Robert A. Casero. Characterization of polyaminohydroxamic acids and polyaminobenzamides as inhibitors of HDAC10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1589.
Abstract 1583: Bcl-6 as a potential therapeutic target for bladder cancer
Authors: Hideki Furuya, Kaoru Murakami, Nari Kim, Charles J. Rosser
Journal: Cancer Research (2023)

Abstract Introduction and Objectives: B-cell lymphoma 6 (Bcl-6) is known to be a nuclear protein and a master transcription factor for regulation of T follicular helper cells (TFH cells) proliferation. Previously, we reported on the increased angiogenic potential of human prostate cancer cells that overexpressed the Bcl-2. Comparative genomic profiling of the endothelial cells treated with/without conditioned media from Bcl-2-overexpressing human prostate cancer cells revealed approximately 250 differentially expressed genes. Interestingly, bioinformatics analysis identified Bcl-6 as one of several secreted proteins on the list. In this study, we first confirmed that Bcl-6 exists in liquid biopsy, and secondly evaluate the effect of Bcl-6 neutralization on angiogenesis and tumor growth in in vitro and in vivo models. Methods: We first analyzed Bcl-6 levels in serum and urine by ELISA. Then we tested the effect of Bcl-6 antibody for the following: ability to inhibit in vitro and in vivo angiogenesis, ability to inhibit cellular proliferation, and tumor growth in cell line-derived xenograft model. Results: First, we found that Bcl-6 exists in urine and serum. Interestingly, Bcl-6 level was significantly higher in cancer patients than healthy subjects. Next, we identified the effective clone tube formation assay. Then we further tested the effect of the antibody and exogenous Bcl-6 on cell proliferation, tube formation, and tube disruption in HUVEC. The exogenous Bcl-6 did not enhance cell proliferation of HUVEC. On the other hand, the Bcl-6 antibody significantly inhibited tube formation in HUVEC, but not tube disruption. Subsequently, we performed Matrigel plug assay to evaluate the effect on angiogenesis in vivo. The CD31 positive cells in Matrigel plug were significantly reduced by the Bcl-6 antibody treatment. To evaluate the effect on tumor growth, we first performed the cell proliferation assay to evaluate the effect on tumor growth in vitro. The Bcl-6 antibody significantly inhibited the cell proliferation of T24 and UM-UC-3 cell lines highly expressing Bcl-6. Finally, we tested the effect of the Bcl-6 antibody on tumor growth in an animal model. Intratumoral injection of Bcl-6 antibody (15 μg/tumor, twice weekly) significantly inhibited the tumor growth. Conclusions: This is the first time to identify that Bcl-6 may be a secreted protein and found that neutralization of Bcl-6 by antibody inhibits angiogenesis and tumor growth in both in vitro and in vivo. The results suggest that neutralizing Bcl-6 by antibody could be a promising therapeutic agent in bladder cancer. Citation Format: Hideki Furuya, Kaoru Murakami, Nari Kim, Charles J. Rosser. Bcl-6 as a potential therapeutic target for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1583.